Characterization of Macrophages and Osteoclasts in the Osteosarcoma Tumor Microenvironment at Diagnosis: New Perspective for Osteosarcoma Treatment?

Biological and histopathological techniques identified osteoclasts and macrophages as targets of zoledronic acid (ZA), a therapeutic agent that was detrimental for patients in the French OS2006 trial. Conventional and multiplex immunohistochemistry of microenvironmental and OS cells were performed on biopsies of 124 OS2006 patients and 17 surgical (“OSNew”) biopsies respectively. CSF-1R (common osteoclast/macrophage progenitor) and TRAP (osteoclast activity) levels in serum of 108 patients were correlated to response to chemotherapy and to prognosis. TRAP levels at surgery and at the end of the protocol were significantly lower in ZA+ than ZA− patients (padj = 0.0011; 0.0132). For ZA+-patients, an increase in the CSF-1R level between diagnosis and surgery and a high TRAP level in the serum at biopsy were associated with a better response to chemotherapy (p = 0.0091; p = 0.0251). At diagnosis, high CD163+ was associated with good prognosis, while low TRAP activity was associated with better overall survival in ZA− patients only. Multiplex immunohistochemistry demonstrated remarkable bipotent CD68+/CD163+ macrophages, homogeneously distributed throughout OS regions, aside osteoclasts (CD68+/CD163−) mostly residing in osteolytic territories and osteoid-matrix-associated CD68−/CD163+ macrophages. We demonstrate that ZA not only acts on harmful osteoclasts but also on protective macrophages, and hypothesize that the bipotent CD68+/CD163+ macrophages might present novel therapeutic targets

Loi du 17 mars 2014 : nouvelles mesures protectrices du consommateur

International audienc

Loi du 17 mars 2014 : nouvelles mesures protectrices du consommateur

International audienc

Naissance de la Chaire Droit de la consommation

International audienc

The Role of Community Pharmacists in the Detection of Clinically Relevant Drug-Related Problems in Chronic Kidney Disease Patients

Community pharmacists (CPs) have traditionally had limited access to patients’ estimated glomerular filtration rate (eGFR) during the medication-dispensing process. The increasing access to shared electronic health records is making eGFR available, but the skills needed to detect and manage clinically relevant drug-related problems (DRPs) are poorly documented. The primary objective of this study was to investigate the role of CPs in the medication-dispensation process for elderly patients with renal impairment. A total of 70 CPs participated in this 6 month study. Community pharmacists asked all patients ≥65 years to bring their laboratory test values for the next medication-dispensing process. Drug-related problem detection rates were compared between CPs (prospective period) and expert pharmacists (retrospectively). The clinical relevance of each DRP was assessed by nephrologists and general practitioners using an appropriate tool. Community pharmacists recruited n = 442 patients with eGFR < 60 mL/min/1.73 m2 and detected n = 99 DRPs, whereas expert pharmacists detected n = 184 DRPs. The most frequently detected DRPs were dosage problems and contraindications. According to assessment by clinicians, CPs and expert pharmacists identified 54.0% and 84.7% of clinically relevant DRPs, respectively. This study suggests a positive impact of the systematic availability of eGFR to CPs on the detection of several DRPs with clinical relevance

BMP-1 disrupts cell adhesion and enhances TGF-β activation through cleavage of the matricellular protein thrombospondin-1

International audienc

CD163-positive tumor-associated macrophages and CD8-positive cytotoxic lymphocytes are powerful diagnostic markers for the therapeutic stratification of osteosarcoma patients: An immunohistochemical analysis of the biopsies fromthe French OS2006 phase 3 trial

International audienceThe French phase 3 trial (OS 2006) testing zoledronic acid, an osteoclast inhibitor, with chemotherapy and surgery did not improve the outcome of patients with osteosarcoma (OS). To understand this unexpected result, the presence of infiltrating immune cells was investigated in 124 pre-therapeutic biopsies of patients enrolled in the trial. The percentage of CD68/CD163 tumor-infiltrating macrophages (TAMs), CD8+ lymphocytes, osteoclasts, and the PD1/PDL-1 checkpoint were assessed by immunohistochemistry. M1/M2 macrophage polarization was characterized by pSTAT1/CMAF staining. The expression of these biomarkers was correlated with clinical outcome. No statistical correlations were found with response to chemotherapy. High CD163 levels (>50% of cells per core; 43.8% of patients) were associated with CMAF nuclear expression and significantly correlated with better overall survival (p = 0.0025) and longer metastasis progression-free survival (MPFS, p = 0.0315) independently of metastatic status (p = 0.002). Only a trend was observed for patients with high CD68-positive cells (p = 0.0582). CD8+ staining was positive in >50% of cases with a median staining of 1%. Lower CD8+ levels were associated with metastatic disease at diagnosis and the presence of CD8-positive cells significantly correlated with improved overall survival in zoledronate-treated patients (p = 0.0415). PD1/PDL-1 staining was negative in >80% of cases and was not correlated with outcome. Finally, CD163-positive TAMs and CD8 positive cells are crucial prognostic biomarkers in OS, whereas PD1/PDL-1 checkpoint plays a minor role. For the first time, we described a correlation between CD8 positive cells and survival in zoledronate-treated patients. The immunohistochemical analysis of the microenvironment in biopsies may represent a novel tool for therapeutic stratification